Multiple regulatory functions of the cyclic nucleotide sensing domain of HCN channels

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The membranes of cells contain receptor proteins that bind natural chemical compounds (messengers) and then respond by switching their molecular structure in order to activate a specific biological function. Other proteins in the membrane switch in response to electric signals (voltage) rather than messengers. We are focusing specifically on receptors called HCN channels which are gated pores enabling transport of ions across the membrane; this gating responds both to voltage and to binding of a messenger called cyclic AMP or cAMP. My group recently discovered that although the domain responsible for cAMP-sensing is situated outside the membrane, this domain nonetheless controls the separate voltage-sensing domain embedded within the membrane. The consequence of this control is modulation of the speed at which the HCN channel pore opens in response to voltage. This is physiologically important because the cAMP messenger is generated by the body under conditions of excitation, such as the "fight-or-flight" adrenaline rush, or during epileptic seizures in some parts of the brain, where timing of a channel response is critical.